SUMMARY: Fragile X syndrome is a debilitating neurogenetic disorder that can result in a multitude of impairments in cognition, memory, and learning. Maladaptive functioning in socio-emotional, cognitive and behavioral domains greatly hinder educational and social development resulting in dysfunction that persists into adulthood. Currently, pharmacological agents such as antipsychotics, antidepressants, and mood stabilizers are recommended in conjunction with behavioral intervention and are focused on symptomatic treatment. In addition to having significant side effects, long term use of these agents can further impede cognitive ability. Therefore, targeted pharmacological treatment is crucial to mitigate these challenges and facilitate optimal development. Recent evidence has brought forth sigma-1 receptor ligands (S1R) as a potential new class of neuroprotective agents. Sigma-1 receptors (S1R) are widely distributed throughout the brain where they interact with ion channels and neurotransmitters and play a critical role in the function of cognition, learning and memory. In this proposal, we will employ our S1R-selective imaging agent, 18F-FTC-146, with positron emission tomography (PET) to begin understanding the functional role of S1Rs in males with FXS. We will translate and explore the utility of clinical- grade 18F-FTC-146 PET-MR imaging to investigate S1R density in males with FXS. Thus, we hypothesize that PET-MR imaging with our highly selective S1R radioligand (18F-FTC-146) will be a useful strategy for studying the potential role of S1Rs for treating FXS. Our imaging approach, utilizing PET and MR imaging, promises to aid clinicians to better develop and select targeted treatments and monitoring treatment response. In addition, it will benefit researchers in multiple disciplines studying the pathophysiology and treatment of FXS and can significantly improve quality of life for families and individuals with intellectual disabilities.